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1.
Haematologica ; 109(8): 2525-2532, 2024 08 01.
Article in English | MEDLINE | ID: mdl-38450522

ABSTRACT

The revised 4th edition of the World Health Organization (WHO4R) classification lists myelodysplastic syndromes with ring sideroblasts (MDS-RS) as a separate entity with single lineage (MDS-RS-SLD) or multilineage (MDS-RS-MLD) dysplasia. The more recent International Consensus Classification (ICC) distinguishes between MDS with SF3B1 mutation (MDS-SF3B1) and MDS-RS without SF3B1 mutation; the latter is instead included under the category of MDS not otherwise specified. The current study includes 170 Mayo Clinic patients with WHO4R-defined MDS-RS, including MDS-RS-SLD (N=83) and MDS-RSMLD (N=87); a subset of 145 patients were also evaluable for the presence of SF3B1 and other mutations, including 126 with (87%) and 19 (13%) without SF3B1 mutation. Median overall survival for all 170 patients was 6.6 years with 5- and 10-year survival rates of 59% and 25%, respectively. A significant difference in overall survival was apparent between MDS-RS-MLD and MDS-RS-SLD (P<0.01) but not between MDS-RS with and without SF3B1 mutation (P=0.36). Multivariable analysis confirmed the independent prognostic contribution of MLD (hazard ratio=1.8, 95% confidence interval: 1.1-2.8; P=0.01) and also identified age (P<0.01), transfusion need at diagnosis (P<0.01), and abnormal karyotype (P<0.01), as additional risk factors; the impact from SF3B1 or other mutations was not significant. Leukemia-free survival was independently affected by abnormal karyotype (P<0.01), RUNX1 (P=0.02) and IDH1 (P=0.01) mutations, but not by MLD or SF3B1 mutation. Exclusion of patients not meeting ICC-criteria for MDS-SF3B1 did not change the observations on overall survival. MLD-based, as opposed to SF3B1 mutation-based, disease classification for MDS-RS might be prognostically more relevant.


Subject(s)
Anemia, Sideroblastic , Mutation , Myelodysplastic Syndromes , Phosphoproteins , RNA Splicing Factors , Humans , RNA Splicing Factors/genetics , Male , Female , Aged , Middle Aged , Prognosis , Aged, 80 and over , Adult , Phosphoproteins/genetics , Anemia, Sideroblastic/genetics , Anemia, Sideroblastic/diagnosis , Anemia, Sideroblastic/mortality , Anemia, Sideroblastic/pathology , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/pathology , Ribonucleoprotein, U2 Small Nuclear/genetics , Cell Lineage , Young Adult
2.
Probl Radiac Med Radiobiol ; 25: 390-401, 2020 Dec.
Article in English, Ukrainian | MEDLINE | ID: mdl-33361849

ABSTRACT

OBJECTIVE: To determine the influence of iron metabolism on the prognosis of acute lymphoblastic (ALL) and (AML)myeloblastic leukemia at the different phases of chemotherapy in children after Chоrnobyl accident. MATERIALS AND METHODS: 333 children (295 - ALL, 38 - AML) were examined at the stages of chemotherapy. Thecomparison group included 93 children without leukemia. Acute leukemia variants, patients survival, relapses, thenature of disease (live child or died), iron methabolism (morphometric parameters of erythrocytes, SI, SF, STf, TS),manifestations of dyserythropoiesis, bone marrow sideroblast and patients radiation dose were taken into account. RESULTS: In 295 patients with ALL the following variants of leukemia were established: pro-B-ALL in 23, «common¼type of ALL in 224, pre-B-ALL in 29, T-ALL in 19. Thirty eight patients were diagnosed with AML (11 - M1, 19 - M2,8 - M4). Doses of radiation in patients with AL were (2.78 ± 0.10) mSv and they did not correlate with clinical andhematological parameters, disease variant. Relapse rates and shorter survival were in patients with T-ALL, pro-B-ALLand AML with SF levels > 500 ng/ml (p < 0.05). The amount of children with normochromic-normocytic anemias andmanifestations of dysplasia of erythroid lineage elements was greater in the AML than in ALL. SF content in patientswas elevated during chemotherapy and was lower than the initial one only in the remission period. Transferrin wasreliably overloaded with iron: TS (70.2 ± 2.3) % compared with the control group (32.7 ± 2.1) %. Correlationbetween TS and survival of patients was detected (rs = -0.45). Direct correlation between the number of iron granules in erythrocariocytes and SF level (rs = 0.43) was established, indicating the phenomena of ineffective erythropoiesis. CONCLUSIONS: The negative influence of iron excess in the patients body on the hemopoiesis function, manifestations of ineffective erythropoiesis and the course of acute leukemia in children have been established. Changes inferrokinetic processes in children can be the basis of leukemоgenesis development.


Subject(s)
Anemia, Sideroblastic/blood , Chernobyl Nuclear Accident , Erythropoiesis/radiation effects , Iron/blood , Leukemia, Myeloid, Acute/blood , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Adolescent , Anemia, Sideroblastic/drug therapy , Anemia, Sideroblastic/etiology , Anemia, Sideroblastic/mortality , Antineoplastic Agents/therapeutic use , Bone Marrow/pathology , Bone Marrow/radiation effects , Child , Child, Preschool , Erythroid Cells/pathology , Erythroid Cells/radiation effects , Female , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/mortality , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Radiation Exposure/adverse effects , Radiation, Ionizing , Recurrence , Remission Induction , Survival Analysis , Transferrin/metabolism , Ukraine/epidemiology
4.
Genes (Basel) ; 11(3)2020 03 14.
Article in English | MEDLINE | ID: mdl-32183361

ABSTRACT

Dog puppy loss by the age of six to eight weeks after normal development is relatively uncommon. Necropsy findings in two spontaneously deceased Belgian Shepherd puppies indicated an abnormal accumulation of material in several organs. A third deceased puppy exhibited mild signs of an inflammation in the central nervous system and an enteritis. The puppies were closely related, raising the suspicion of a genetic cause. Pedigree analysis suggested a monogenic autosomal recessive inheritance. Combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 13 genome segments totaling 82 Mb. The genome of an affected puppy was sequenced and compared to 645 control genomes. Three private protein changing variants were found in the linked and homozygous regions. Targeted genotyping in 96 Belgian Shepherd dogs excluded two of these variants. The remaining variant, YARS2:1054G>A or p.Glu352Lys, was perfectly associated with the phenotype in a cohort of 474 Belgian Shepherd dogs.YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase 2 and the predicted amino acid change replaces a negatively charged and evolutionary conserved glutamate at the surface of the tRNA binding domain of YARS2 with a positively charged lysine. Human patients with loss-of-function variants in YARS2 suffer from myopathy, lactic acidosis, and sideroblastic anemia 2, a disease with clinical similarities to the phenotype of the studied dogs. The carrier frequency was 27.2% in the tested Belgian Shepherd dogs. Our data suggest YARS2:1054G>A as the candidate causative variant for the observed juvenile mortality.


Subject(s)
Anemia, Sideroblastic/genetics , Cardiomyopathies/genetics , Dog Diseases/genetics , Tyrosine-tRNA Ligase/genetics , Anemia, Sideroblastic/mortality , Anemia, Sideroblastic/veterinary , Animals , Cardiomyopathies/mortality , Cardiomyopathies/veterinary , Central Nervous System/metabolism , Central Nervous System/pathology , Dog Diseases/mortality , Dog Diseases/pathology , Dogs , Genes, Recessive/genetics , Genetic Linkage , Genome/genetics , Mutation, Missense/genetics , Pedigree
6.
Leukemia ; 31(3): 720-727, 2017 03.
Article in English | MEDLINE | ID: mdl-27604819

ABSTRACT

Heterozygous somatic mutations affecting the spliceosome gene SF3B1 drive age-related clonal hematopoiesis, myelodysplastic syndromes (MDS) and other neoplasms. To study their role in such disorders, we generated knock-in mice with hematopoietic-specific expression of Sf3b1-K700E, the commonest type of SF3B1 mutation in MDS. Sf3b1K700E/+ animals had impaired erythropoiesis and progressive anemia without ringed sideroblasts, as well as reduced hematopoietic stem cell numbers and host-repopulating fitness. To understand the molecular basis of these observations, we analyzed global RNA splicing in Sf3b1K700E/+ hematopoietic cells. Aberrant splicing was associated with the usage of cryptic 3' splice and branchpoint sites, as described for human SF3B1 mutants. However, we found a little overlap between aberrantly spliced mRNAs in mouse versus human, suggesting that anemia may be a consequence of globally disrupted splicing. Furthermore, the murine orthologues of genes associated with ring sideroblasts in human MDS, including Abcb7 and Tmem14c, were not aberrantly spliced in Sf3b1K700E/+ mice. Our findings demonstrate that, despite significant differences in affected transcripts, there is overlap in the phenotypes associated with SF3B1-K700E between human and mouse. Future studies should focus on understanding the basis of these similarities and differences as a means of deciphering the consequences of spliceosome gene mutations in MDS.


Subject(s)
Anemia, Sideroblastic/etiology , Anemia, Sideroblastic/pathology , Hematopoiesis/genetics , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/genetics , Phosphoproteins/genetics , RNA Splicing Factors/genetics , RNA Splicing , Anemia, Sideroblastic/mortality , Animals , Disease Models, Animal , Gene Targeting , Humans , Mice , Mice, Transgenic , Mutation , Phenotype , RNA Splicing Factors/metabolism
7.
Leuk Lymphoma ; 58(7): 1686-1693, 2017 07.
Article in English | MEDLINE | ID: mdl-27771989

ABSTRACT

The incidence of SF3B1 mutations in patients with RARS is high. Recently, it has been shown that SF3B1 and DNMT3A mutations overlap more often than expected, although it is not clear how this could affect the disease. We studied SF3B1 and DNMT3A in 123 RARS patients: 101 out of 123 samples (82%) had somatic mutations in SF3B1, and 13 of them (13%) showed a co-mutation (SF3B1mutDNMT3Amut). All co-mutated patients had a normal karyotype, and 12 of them (92%) were lower-risk patients (IPSS and IPSS-R). Despite their favorable profile, SF3B1mutDNMT3Amut patients showed a higher RBC transfusion dependency (92% versus 48%, p = .007), a shorter overall survival (OS) (median, 30 versus 97 months, p = .034), and a higher risk of progression to acute myeloid leukemia (AML) at 5 years (25% versus 2%, p = .023) than SF3B1mutDNMT3Awt patients. In conclusion, DNMT3A mutations are present in a significant proportion of SF3B1mut patients with a negative clinical impact.


Subject(s)
Anemia, Refractory/genetics , Anemia, Refractory/mortality , Anemia, Sideroblastic/genetics , Anemia, Sideroblastic/mortality , DNA (Cytosine-5-)-Methyltransferases/genetics , Mutation , Phosphoproteins/genetics , RNA Splicing Factors/genetics , Adult , Aged , Aged, 80 and over , Anemia, Refractory/diagnosis , Anemia, Sideroblastic/diagnosis , Chromosome Aberrations , DNA Methyltransferase 3A , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Phenotype , Prognosis
8.
Leuk Res ; 44: 8-16, 2016 May.
Article in English | MEDLINE | ID: mdl-26970172

ABSTRACT

OBJECTIVE: To clarify the possible biological differences and implication of the SF3B1 gene for patients with MDS-RS (myelodysplastic syndromes with ring sideroblasts). METHODS: Sanger sequencing was performed on mutation hotspots of the SF3B1 gene in MDS-RS patients. The differences between the SF3B1 mutated and wild-type subsets, including the ultrastructure of erythroid precursors, iron profile parameters, erythropoiesis-related measurements, as well as clinical features, were analyzed. RESULTS: SF3B1 mutations were detected in 33 out of fifty-two MDS-RS patients (63%). The vast majority of patients with mutations (94%) were categorized in the lower risk group according to the IPSS (International Prognostic Scoring System), in contrast to only fifty-eight percent of the wild-type cases. In addition to the notably higher percentages of erythroblasts and ring sideroblasts in patients with mutations, abundant electron-dense granules in the mitochondria of the erythroid precursors were clearly observed. Moreover, patients with mutations presented both improper iron uptake and distribution (lower serum hepcidin-25 concentration, P=0.028) and enhanced erythropoietic activity (higher soluble transferrin receptor level, P=0.132; higher growth differentiation factor 15 concentration, P<0.001). Finally, MDS-RS patients carrying SF3B1 mutations had a better overall survival (median 38 vs. 18 months, P=0.001) compared to those without mutations. By multivariable analysis, the prognostic significance of the SF3B1 mutation was primarily accounted for by IPSS risk categorization. CONCLUSION: MDS-RS patients carrying SF3B1 mutations harbored a more severe iron overload and corresponding over-erythropoiesis. The better overall survival of SF3B1-mutated MDS-RS patients may be mainly due to the clustering of patients with lower risk disease in this group.


Subject(s)
Anemia, Sideroblastic/genetics , Erythropoiesis/genetics , Iron Overload/pathology , Mutation/genetics , Myelodysplastic Syndromes/genetics , Phosphoproteins/genetics , Ribonucleoprotein, U2 Small Nuclear/genetics , Adult , Aged , Aged, 80 and over , Anemia, Sideroblastic/mortality , Anemia, Sideroblastic/pathology , Biomarkers, Tumor/genetics , Female , Follow-Up Studies , Humans , Iron Overload/genetics , Iron Overload/mortality , Male , Middle Aged , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/pathology , Neoplasm Staging , Prognosis , RNA Splicing Factors , Survival Rate , Young Adult
9.
Am J Hematol ; 91(5): 492-8, 2016 May.
Article in English | MEDLINE | ID: mdl-26874914

ABSTRACT

Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had ≥1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n = 82), anemia (P = 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P =.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n = 48), univariate analysis showed association between poor survival and presence of SETBP1 (P = 0.04) or ASXL1 (P = 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P = 0.04); the number of concurrent mutations did not provide additional prognostication (P = 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high (≥2 points), with median survivals of 80, 42 and 11 months respectively (P = 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutation-enhanced prognostic model.


Subject(s)
Anemia, Refractory, with Excess of Blasts/mortality , Anemia, Sideroblastic/mortality , Codon, Nonsense , DNA Mutational Analysis/methods , Frameshift Mutation , Sequence Analysis, DNA/methods , Thrombocytosis/etiology , Aged , Aged, 80 and over , Anemia, Refractory, with Excess of Blasts/complications , Anemia, Refractory, with Excess of Blasts/genetics , Anemia, Sideroblastic/complications , Anemia, Sideroblastic/genetics , Bone Marrow/chemistry , Bone Marrow/pathology , Carrier Proteins/genetics , Chromosome Aberrations , Disease Progression , Female , Hemoglobins/analysis , Humans , Janus Kinase 2/genetics , Kaplan-Meier Estimate , Karyotyping , Male , Middle Aged , Nuclear Proteins/genetics , Phosphoproteins/genetics , Prognosis , Proportional Hazards Models , RNA Splicing Factors , Repressor Proteins/genetics , Ribonucleoprotein, U2 Small Nuclear/genetics , Thrombocytosis/genetics
10.
Eur J Haematol ; 94(5): 413-8, 2015 May.
Article in English | MEDLINE | ID: mdl-25200248

ABSTRACT

TET2, a member of the ten-eleven-translocation (TET) family genes that modify DNA by converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), is located in chromosome 4q24 and is frequently mutated in myeloid malignancies. The impact of TET2 mutation on survival outcomes is still controversial; however, functional studies have proved that it is a loss-of-function mutation that impairs myeloid cell differentiation and contributes to the phenotype of myeloid neoplasia. We, herein, aimed to investigate TET2 expression in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). A significantly decreased TET2 expression was observed in bone marrow cells from AML (n = 53) and patients with MDS (n = 64), compared to normal donors (n = 22). In MDS, TET2 expression was significantly reduced in RAEB-1/RAEB-2 compared to other WHO 2008 classifications, and a lower TET2 expression was observed at the time of MDS disease progression in four of five patients. In multivariate analysis, low TET2 expression (P = 0.03), male gender (P = 0.02), and WHO 2008 classification (P < 0.0001) were independent predictors of poorer overall survival. These results suggest that defective TET2 expression plays a role in the MDS pathophysiology and predicts survival outcomes in this disease.


Subject(s)
Anemia, Refractory, with Excess of Blasts/genetics , Anemia, Sideroblastic/genetics , DNA-Binding Proteins/genetics , Leukemia, Myeloid, Acute/genetics , Proto-Oncogene Proteins/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Anemia, Refractory, with Excess of Blasts/diagnosis , Anemia, Refractory, with Excess of Blasts/mortality , Anemia, Refractory, with Excess of Blasts/pathology , Anemia, Sideroblastic/diagnosis , Anemia, Sideroblastic/mortality , Anemia, Sideroblastic/pathology , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Case-Control Studies , Chromosomes, Human, Pair 4 , Dioxygenases , Down-Regulation , Female , Gene Expression , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Multivariate Analysis , Mutation , Prognosis , Survival Analysis
11.
Cytometry B Clin Cytom ; 84(3): 194-7, 2013 May.
Article in English | MEDLINE | ID: mdl-23283847

ABSTRACT

BACKGROUND: Within the myelodysplastic/myeloproliferative neoplasm (MDS/MPN) category of the WHO (2008), only chronic myelomonocytic leukemia was so far evaluated by multiparameter flow cytometry (MFC). METHODS: To investigate the potential of MFC for MDS/MPNs, unclassifiable (MDS/MPNu), and refractory anemia associated with ring sideroblasts and marked thrombocytosis (RARS-T), we studied 91 patients with these entities (60 males/31 females; 35.3-87.4 years) for MDS-related aberrant immunophenotypes (≥ 2 different cell lineages with ≥ 3 aberrantly expressed antigens). Data were correlated with cytomorphology and cytogenetics. RESULTS: MFC identified MDS-related immunophenotypes in 54/91 (59.3%) of patients. Patients with or without MDS-related immunophenotype did not differ significantly by demographic characteristics, blood values, or median overall survival. MDS-related immunophenotype cases showed a higher number of aberrantly expressed antigens (mean ± SD, 4.9 ± 2.4 vs. 2.0 ± 1.4; P < 0.001). Aberrant karyotypes showed a similar frequency in patients with and without MDS-related immunophenotype (11/54; 20.4% vs. 7/37; 18.9%; P = n.s.). CONCLUSIONS: MDS-related immunophenotype are present in more than half of patients with MDS/MPNu and RARS-T. MFC therefore may be helpful to separate cases into more "MDS-like" or "MPN-like" subgroups.


Subject(s)
Anemia, Refractory/diagnosis , Anemia, Sideroblastic/diagnosis , Antigens, CD/genetics , Flow Cytometry/methods , Myelodysplastic Syndromes/diagnosis , Myeloproliferative Disorders/diagnosis , Adult , Aged , Aged, 80 and over , Anemia, Refractory/genetics , Anemia, Refractory/mortality , Anemia, Refractory/pathology , Anemia, Sideroblastic/genetics , Anemia, Sideroblastic/mortality , Anemia, Sideroblastic/pathology , Antigens, CD/immunology , Cytogenetic Analysis , Diagnosis, Differential , Erythroid Cells/immunology , Erythroid Cells/pathology , Female , Gene Expression , Humans , Immunophenotyping , Male , Middle Aged , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/pathology , Myeloid Cells/immunology , Myeloid Cells/pathology , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/mortality , Myeloproliferative Disorders/pathology , Survival Analysis
12.
Leuk Res ; 36(7): 826-31, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22554895

ABSTRACT

In 2008, the WHO combined the former categories RCMD (refractory cytopenia with multilineage dysplasia) and RCMD-RS (ring sideroblasts ≥ 15%). We studied the clinical impact and genetic background of RARS, RCMD, and RCMD-RS in 1082 patients. Good karyotypes (IPSS) were similarly frequent in RARS, RCMD, and RCMD-RS. 2-year overall survival (OS) rates were similar in RARS, RCMD, and RCMD-RS (85.9%/89.0%/91.7%; n.s.). The 2-year OS rate was better in good than intermediate or poor karyotypes (p<0.001). These results support to combine RCMD and RCMD-RS as performed by WHO and emphasize the prognostic power of cytogenetic criteria for these MDS subtypes.


Subject(s)
Anemia, Refractory/diagnosis , Anemia, Sideroblastic/diagnosis , Myelodysplastic Syndromes/classification , Myelodysplastic Syndromes/diagnosis , Adult , Aged , Aged, 80 and over , Anemia, Refractory/epidemiology , Anemia, Refractory/genetics , Anemia, Refractory/mortality , Anemia, Sideroblastic/epidemiology , Anemia, Sideroblastic/genetics , Anemia, Sideroblastic/mortality , Cohort Studies , Cytogenetics/methods , Female , Humans , Male , Middle Aged , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/mortality , Prognosis , Survival Analysis , Young Adult
13.
Haematologica ; 97(7): 1036-41, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22532522

ABSTRACT

BACKGROUND: Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm and to compare its clinical outcome with that of refractory anemia with ring sideroblasts and essential thrombocythemia. DESIGN AND METHODS: We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis. For each of these patients, each patient diagnosed with refractory anemia with ring sideroblasts was matched for age and sex. At the same time, a cohort of 454 patients with essential thrombocythemia was used to compare outcomes of the two diseases. RESULTS: In patients with refractory anemia with ring sideroblasts and marked thrombocytosis, depending on the Janus Kinase 2 V617F mutational status (positive or negative) or platelet threshold (over or below 600 × 10(9)/L), no difference in survival was noted. However, these patients had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia (P<0.001) but better survival (P<0.001) and a higher risk of thrombosis (P=0.039) than patients with refractory anemia with ring sideroblasts. CONCLUSIONS: The clinical course of refractory anemia with ring sideroblasts and marked thrombocytosis is better than that of refractory anemia with ring sideroblasts and worse than that of essential thrombocythemia. The higher risk of thrombotic events in this disorder suggests that anti-platelet therapy might be considered in this subset of patients. From a clinical point of view, it appears to be important to consider refractory anemia with ring sideroblasts and marked thrombocytosis as a distinct entity.


Subject(s)
Anemia, Refractory/pathology , Anemia, Sideroblastic/pathology , Janus Kinase 2/genetics , Thrombocythemia, Essential/pathology , Thrombocytosis/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Anemia, Refractory/complications , Anemia, Refractory/mortality , Anemia, Sideroblastic/complications , Anemia, Sideroblastic/mortality , Blood Platelets/pathology , Europe , Female , Humans , Male , Middle Aged , Mutation , Platelet Count , Retrospective Studies , Risk Factors , Survival Analysis , Thrombocythemia, Essential/complications , Thrombocythemia, Essential/mortality , Thrombocytosis/complications , Thrombocytosis/mortality
14.
Blood ; 119(2): 569-72, 2012 Jan 12.
Article in English | MEDLINE | ID: mdl-22096241

ABSTRACT

SF3B1 mutations were recently reported in myelodysplastic syndromes (MDSs), especially in the presence of ring sideroblasts (RSs). We sought to define the interaction between SF3B1 mutations, morphology, karyotype, and prognosis in MDS with more than or equal to 15% RS (MDS-RS). We studied 107 patients with MDS-RS, including 48 with refractory anemia with RS (RARS), 43 with refractory cytopenia with multilineage dysplasia (RCMD)-RS, 11 with refractory anemia with excess blasts-1 (RAEB1)-RS, and 5 with RAEB2-RS. SF3B1 mutations were detected in 53 (∼ 50%) patients: 35 RARS (73%), 16 RCMD-RS (37%), and 2 RAEB1-RS (18%). In univariate analysis, the presence of SF3B1 mutations was associated with better overall (P < .01) and leukemia-free (P < .01) survival; however, in both instances, significance was completely accounted for by World Health Organization morphologic risk categorization. In other words, when RARS and RCMD-RS were analyzed separately, there was no additional prognostic value from the presence or absence of SF3B1 mutations.


Subject(s)
Anemia, Refractory/genetics , Anemia, Sideroblastic/genetics , Mutation/genetics , Myelodysplastic Syndromes/genetics , Phosphoproteins/genetics , Ribonucleoprotein, U2 Small Nuclear/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Anemia, Refractory/epidemiology , Anemia, Refractory/mortality , Anemia, Sideroblastic/epidemiology , Anemia, Sideroblastic/mortality , DNA Mutational Analysis , Female , Humans , Male , Middle Aged , Myelodysplastic Syndromes/epidemiology , Myelodysplastic Syndromes/mortality , Polymerase Chain Reaction , Prevalence , Prognosis , RNA Splicing Factors , Survival Rate , Young Adult
15.
Am J Hematol ; 83(8): 611-3, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18442062

ABSTRACT

In a retrospective study of 126 adult patients with French-American-British-defined refractory anemia with ringed sideroblasts (RARS), staging by the International Prognostic Scoring System was highly predictive of survival outcome (P < 0.0001). In addition, red blood cell (RBC) transfusion requirement at diagnosis (P = 0.001), but not the number of RBC units transfused during the disease course (P = 0.17), was independently associated with inferior survival. There were no correlations between survival and serum ferritin level, measured either at diagnosis (median 567 ng/mL, range 16-3,475; P = 0.24) or during follow-up (median 1,108 ng/mL; range 238-43,500; P = 0.72). Similarly, there was no difference in survival when patients were stratified by serum ferritin levels of < or > or =1,000 ng/mL at diagnosis or peak serum ferritin levels of <1,000, 1,000-5,000, or >5,000 ng/mL during follow-up. The current study does not support the contention that transfusional hemosiderosis is an adverse prognostic factor in "good risk" myelodysplastic syndrome.


Subject(s)
Anemia, Sideroblastic/diagnosis , Anemia, Sideroblastic/mortality , Erythrocyte Transfusion , Ferritins/blood , Adult , Aged , Aged, 80 and over , Cause of Death , Female , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Survival Analysis , Survival Rate
16.
Ann Hematol ; 85(8): 502-13, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16715299

ABSTRACT

We retrospectively studied 89 consecutive patients diagnosed with primary myelodysplastic syndrome (MDS) over a period of 10 years to (1) identify prognostic factors for overall survival (OS) and leukemia-free survival (LFS); (2) to assess and compare the Bournemouth-, Spanish-, Düsseldorf-, Lille-, and the International prognostic scoring systems (IPSS); and to (3) compare the French-American-British (FAB) and World Health Organization (WHO) classifications. The median age of patients was 63 years (range, 26-85). Karyotype analyses were done in 85 patients (96%). Median OS was 3 years; 67 patients (75%) have died, and 28 (31%) had progression to acute myeloid leukemia (AML). Major independent prognostic variables for both OS and LFS (multivariate analysis) were percentage of bone marrow (BM) blasts (P < 0.0001), and in patients with cytogenetic data available, cytogenetic risk groups by Lille-score (OS, P = 0.031/LFS, P = 0.002) and IPSS (OS, P = 0.024). All five prognostic scoring systems successfully discriminated risk groups as regards OS and LFS, but in patients with cytogenetic data available, the major independent prognostic score for OS (P < 0.0001) and LFS (P = 0.006) was the IPSS. The FAB and WHO classifications also successfully discriminated between risk groups. The new WHO subgroups [refractory cytopenia with multilineage dysplasia (RCMD), with (RCMD-RS) or without ringed sideroblasts] showed a significantly (P = 0.0454) different prognosis for OS, but not for LFS (P = 0.0839), in comparison to the subgroups having erythroid dysplasia only (RA/RARS). Risk stratification into refractory anemia with excess blast-I (RAEB-I) and RAEB-II tended to yield different prognoses for OS and LFS. The 5q-minus syndrome strongly predicted for a good prognosis. In patients treated with the demethylating agent decitabine (n = 24), IPSS "poor risk" cytogenetics were unable to predict for the expected worse prognosis when compared to "intermediate-risk" cytogenetics. In conclusion, we confirm in a single-center patient cohort that the use of the WHO classification improves the predictive value of the FAB classification and that, in patients with cytogenetic data available, the IPSS can be used for clinical decision-making.


Subject(s)
Anemia, Refractory, with Excess of Blasts , Anemia, Sideroblastic , Adult , Aged , Aged, 80 and over , Anemia, Refractory, with Excess of Blasts/diagnosis , Anemia, Refractory, with Excess of Blasts/mortality , Anemia, Sideroblastic/diagnosis , Anemia, Sideroblastic/mortality , Disease-Free Survival , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Factors , Survival Rate , World Health Organization
17.
Br J Haematol ; 131(2): 180-4, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16197447

ABSTRACT

Sideroblastic anaemia with ringed sideroblasts and marked thrombocytosis, hereupon referred to as ringed sideroblasts with thrombocytosis (RST), is a provisional entity in the 2001 World Health Organisation classification scheme. This retrospective study identified 16 patients with RST over a 7-year period. Proposed diagnostic criteria include a sustained platelet count > 500 x 10(9)/l, > or = 15% ringed sideroblasts, < 3% bone marrow blasts, and normal conventional cytogenetics. The median age was 76 years with eight males and eight females. With a median follow-up of 41 months, RST patients had a median overall survival of 71 months, comparable with refractory anaemia having ringed sideroblasts, but less favourable than essential thrombocythaemia. Thus far, no patients with RST are known to have died of disease-related causes. Patients with ringed sideroblasts and/or thrombocytosis need to be carefully evaluated for a variety of haematological diseases that may confer significantly different prognoses.


Subject(s)
Anemia, Sideroblastic/classification , Myelodysplastic Syndromes/classification , Myeloproliferative Disorders/classification , Thrombocytosis/classification , Adult , Aged , Analysis of Variance , Anemia, Sideroblastic/diagnosis , Anemia, Sideroblastic/mortality , Cytogenetic Analysis , Female , Flow Cytometry , Humans , Male , Megakaryocytes/pathology , Middle Aged , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/mortality , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/mortality , Platelet Count , Retrospective Studies , Statistics, Nonparametric , Survival Analysis , Thrombocytosis/diagnosis , Thrombocytosis/mortality
18.
Leuk Res ; 28(6): 587-94, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15120935

ABSTRACT

The WHO classification for myelodysplastic syndromes (MDS) has introduced new categories with prognostic relevance. Our aim was to examine the predictive value of the WHO and the FAB classification compared to parameters of peripheral blood, bone marrow and IPSS. Clinical data, peripheral blood counts, bone marrow (BM) cytology and histology and survival were analyzed in consecutive newly diagnosed adult patients with MDS. All cases were diagnosed according to FAB criteria and reclassified by the WHO proposal. Among 150 patients entering the study median age was 58 years (12-90). According to FAB, 90 patients had refractory anemia (RA), 18 sideroblastic anemia, 34 refractory anemia with excess of blasts (RAEB), three RAEB-t and five chronic myelomonocytic leukemia. Using the WHO proposal, one half of the patients with RA changed category. One patient had the 5q-syndrome. There were 25 cases with refractory cytopenias with multilineage dysplasia (RCMD) and 23 WHO "unclassified". These last patients presented few cell atypias, favorable IPSS and a good survival as has been described for refractory cytopenias in pediatric MDS. Hypocellular BM was found in 24% of the patients. Karyotype was available in only 85 cases. In the univariate analysis, both classifications, hemoglobin values, hypercellular bone marrow and IPSS had an influence on survival. Using the bootstrap resampling as stability test for the model created by the multivariate analysis, the WHO classification entered the model in 73%, FAB in 38% and IPSS in only 7%. Therefore, in a setting with a high number of low-risk MDS, the WHO classification is the best predictor of survival of the patients.


Subject(s)
Myelodysplastic Syndromes/mortality , Adolescent , Adult , Aged , Aged, 80 and over , Anemia, Refractory/classification , Anemia, Refractory/mortality , Anemia, Refractory, with Excess of Blasts/classification , Anemia, Refractory, with Excess of Blasts/mortality , Anemia, Sideroblastic/classification , Anemia, Sideroblastic/mortality , Blood Cell Count , Bone Marrow/pathology , Brazil/epidemiology , Cell Lineage , Child , Female , Humans , Karyotyping , Male , Middle Aged , Myelodysplastic Syndromes/classification , Survival Rate , World Health Organization
20.
Haematologica ; 87(4): 392-9, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11940483

ABSTRACT

BACKGROUND AND OBJECTIVES: According to the recently published WHO-classification essential thrombocythemia with ringed sideroblasts (ET/RS) remains an ambiguous category which may be considered as myelodysplastic/myeloproliferative disease, unclassifiable. Because until now only case reports or very small series of patients have been described, a more systematically performed study is warranted. DESIGN AND METHODS: A retrospective evaluation was carried out on 38 patients with the diagnosis of ET/RS and more than 15 % ringed sideroblasts on smears. Simultaneously performed bone marrow biopsies, follow-up examinations and survival data were also available. RESULTS: Based on cytological features and particular bone marrow findings including immunohistochemistry three patterns could be determined. These were associated with different clinical features and in particular prognosis. Group I included six patients whose diagnosis was consistent with ET, group II comprised 21 patients revealing prefibrotic and early fibrotic chronic idiopathic myelofibrosis (CIMF) and finally 11 patients (group III) displayed myelodysplastic syndromes (MDS). Follow-up studies revealed that no patient with ET showed a fiber increase but eight CIMF patients developed overt myelofibrosis and four patients of the MDS group developed secondary acute myeloid leukemia. In comparison with a control group of 39 patients with true ET, prognosis was significantly different because our cohort showed a median survival of 100 months that contrasted significantly with the 170 months in the patients with true ET. INTERPRETATION AND CONCLUSIONS: Ringed sideroblasts are not a pathognomonic feature of MDS, but may indicate a dysplasia probably associated with a primary or secondary disturbance of iron metabolism in a variety of disorders. For this reason, a more accurate classification of so-called ET/RS patients is warranted by evaluation of smears and in particular bone marrow biopsy specimens. According to our findings these patients should be classified as having either ET, CIMF or MDS and show a significantly different survival pattern.


Subject(s)
Anemia, Sideroblastic/classification , Thrombocythemia, Essential/classification , Aged , Aged, 80 and over , Anemia, Sideroblastic/mortality , Anemia, Sideroblastic/pathology , Cohort Studies , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Myelodysplastic Syndromes/classification , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/pathology , Myeloproliferative Disorders/classification , Myeloproliferative Disorders/mortality , Myeloproliferative Disorders/pathology , Retrospective Studies , Survival Analysis , Thrombocythemia, Essential/mortality , Thrombocythemia, Essential/pathology , World Health Organization
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